The stimulation of neural cells can be reduced by improving the inhibited synapse caused by gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter of brain, and the anticonvulsant agents that inhibit GABA aminotransferase by which GABA is decomposed are expected to be used in developed countries in the near future. Particularly, a number of studies are conducted on γ-hydroxybutyric acid as a GABA neurotransmitter drug. GHB is a substance produced as a metabolite of γ-aminobutyric acid in brain, and because it functions as a neurotransmitter and a neuroregulator, the GHB has been clinically used as a therapeutic agent for cataplexy and narcolepsy, sedative, and treatment of alcoholism. In particular, the epileptic seizure that is completely blocked by the GHB in a mouse is known to be the best pharmacological model of viable antiepileptic drug for human use.
A γ-hydroxybutyric acid (4-hydroxybutanoic acid, C4H8O3), commonly abbreviated as GHB, is an endogenous substance, and a natural substance found in low amount in central nervous system, grapevine, beef, small citrus fruits and most other organisms. It is currently regulated in the United States, and marketed by Jazz Pharmaceuticals under the trade name, Xyrem.
However, γ-hydroxybutyric acid (GHB) is also an illegal chemical that is recognized as a major cause of drug related coma in the United States and other countries. As a matter of fact, the reported number of GHB overdose in the United States currently outweighs that of MDMA (ecstasy).
GHB, which also functions as a sedative of central nervous system (CNS) in a non-medical fashion is abused. Its various common names include liquid ecstasy and liquid X. GHB may induce the state of euphoria, hyperactivity and increase in enjoyment of music, increase in sexual desire, and increase in sociality at relatively low dose. At relatively high dose, GHB may induce nausea, dizziness, drowsiness, anxiety, visual disorder, hypoventilation, amnesia, unconsciousness, and death. The effect of GHB can persist 1.5 to 3 hours or longer if high dose is consumed or mixed with alcohol.
Some chemicals are converted into GHB in a stomach and during blood circulation. GBL or γ-butyrolactone is one of these prodrugs. Other prodrugs include 1,4-butanediol(1,4-B). The precursors thereof may include additional toxicity.
Although GHB was initially synthesized in France more than 40 years ago as an available anesthetic, it was rejected by medical institutes of the United States due to undesirable side effects. As more countries became aware of the above-described issue, the legalized use thereof is diminishing in most places. GHB is an orphan drug that was studied to treat complex disease of sleep disorders publicly known as hypnolepsy/cataplexy and was made public in 1987. At nearly the same time, the steroid users were informed that GHB may boost the production of growth hormone in body (in the state of deep sleep). However, due to the increased frequency of overdose, its marketing was interrupted in November, 1990. As a result of stricter regulation imposed on GHB, its homologues or related chemicals that can be converted to GHB in body have gained more popularity.
As conventional technologies to replace the above-described GHB, the chemicals containing the first residue that is covalently bonded to the second residue through amino terminal or acidic terminal other than a carboxylic acid group and the second residue, in which the first residue is an analogue or a derivative of γ-aminobutyric acid (GABA) or GABA, is described in International Application No. WO 2010/042759 and in Korean Patent No. 957772, the high 4HB producing mutant to which the genes encoding enzymes that convert succinate to 4HB (4-hydroxybutyrate) are introduced and lacking the genes encoding enzymes that convert succinate semialdehyde to succinate and the preparation method of 4HB using the mutant are described.
However, the development of a therapeutic agent that can substitute GHB, can be safely administered due to alcohol insolubility, and has the similar treatment effect to that of GHB is still required.